Closing date: 03/02/2023
MB-PhD Project: Engineering TIL to Overcome Glucose Competition In the Ovarian Tumour Microenvironment
Initial Intercalation Deadline: 12 December 2022
Interviews: Tuesday 7 March 2023
Final Deadline for Permission to Intercalate (UoM Programmes): 26 May 2023
MB-PhD Start Date: September 2023
Project Keywords:TIL therapy, alternative carbon source, ovarian cancer
Research Opportunity: Intercalated PhD, leading to the award of PhD and MBChB
Applications for this project are now open. Candidates must contact prospective supervisor/s ahead of submitting an application. See the MB-PhD programme page for details of how to apply.
Tumour infiltrating lymphocytes (TIL) are a critical component of the body’s immune response to cancer. They limit cancer development and augment response to a range of therapeutics. The infusion of ex vivo expanded autologous TIL in melanoma patients has been shown to lead to complete and durable tumour regression in a significant fraction of patients and we are currently recruiting patients to TIL trials across a range of tumour types in Manchester. However, complete responses occur in only a minority of patients, indicating that TIL therapy is suboptimal. A factor inhibiting TIL activity in the solid tumour environment is access to nutrients due to poor tumour vascularisation and competition with tumour and stromal cells for nutrients, and notably access to sufficient glucose which is essential for T cell activation.
Through the proposed research the student will evaluate whether alternative carbon sources (ACS) recently shown to be utilisable by T cells can enhance TIL activity in low glucose concentrations. The student will also address whether the ability of TIL to utilise these ACS can be further enhanced by engineering them to express enzymes implicated in the import or catabolism of these ACS, thereby armouring TIL to function in the solid tumour environment. The Edmondson laboratory has shown that TIL can be readily harvested from resected ovarian cancer and expanded ex vivo and has generated a biobank of matched autologous ovarian cultures and TIL. The Hurlstone laboratory has established a platform for engineering T cells using viral constructs. This project utilizes the knowledge and skill base of the supervisor’s teams to innovate TIL therapy with a line of sight to the clinical trials being undertaken in Manchester.
About the Hurlstone Lab
“I am a cancer biologist based in the Michael Smith building on the university’s central campus, which provides excellent physical space, cutting edge research facilities, and a stimulating intellectual environment. My co-supervisor Professor Edmondson is a gynaecological surgeon, specializing in ovarian cancer. His laboratory is located in nearby St Mary’s hospital, sited for optimal access to surgical theatres. The Hurlstone and Edmondson laboratories comprise several post-doctoral research associates, clinical research fellows, PhD students, Masters students and undergraduates performing laboratory-based research who support training at the bench. Professor Thistlethwaite runs an extensive clinical and translational programme at The Christie for adoptive cell therapy in solid tumours. She is the Director of the multi partner iMATCH consortium”.
“Both I and Prof Edmondson have extensive experience in supervising PhD students, including clinicians. As a former MB-PhD student herself, Prof Thistlethwaite has personal insight into the particular needs of MB-PhD students. A successful applicant will receive regular guidance from her/his supervisory team through one-to-one meetings and also from peers at group meetings. These meetings provide regular opportunities for students to discuss data and receive feedback and help with troubleshooting. They also provide a forum for practicing talks and discussing literature”.
Publications and Existing Literature
“The primary goal of the student is to complete their doctoral thesis and successfully defend it in an oral exam (viva). Most students in Hurlstone and Edmondson laboratories also publish their research in leading scientific journals and present their research as posters or oral presentations at national and international meetings”.
“Students participate in a faculty-wide graduate training program designed to enhance transferable skills such as abstract writing, poster and oral presentation, and science communication. Faculty, school and department organize several meetings, affording students further opportunity to present their research. An MB-PhD enhances career prospects within academic medicine, but the primary motivation should be intellectual curiosity and a passion for research”.
“The research vocation requires commitment, flexibility and consistent effort but this should be compatible with a good work-life balance”.
Find out more about the MB-PhD Programme in Manchester and our current MB-PhD students.